Developing a novel therapy, combining RIT with conventional therapy, for treatment of advanced colorectal cancer

Bowel cancer is the third most common cancer in the UK ( 38,000 new cases/year), with more than 50% of those patients eventually dying of their disease. Radioimmunotherapy (RIT), uses a man-made molecule that is exactly like an antibody that we would make to fight the bacteria that infect us sometimes, except it is designed to bind to foreign cancer cells rather than bacterial cells. The cancer targeting antibody can be linked to radioactivity and injected into the patient, where it becomes able to kill cancer cells wherever they are in the body. This method has been partly successful in some patients in clinical trials. However, the cancer sometimes regrows, because the antibody and radiation cannot get to all cells and some that are bombarded with radiation, seem to survive. It is not possible to inject more of the radiolabeled antibody as the increased radiation would also affect the cells in the bloodstream and our normal white cells that protect us from infection. Our previous research showed that when we combined RIT, with another antibody which also targets colorectal cancer, the effect of the radiation from the radiolabeled antibody increased, and animals with tumours were cured. We plan to experiment with the amount of the two antibodies, and the times that they are given, so that the schedule for the combined antibody therapy is ready to be given to patients as part of a clinical trial within 3 years.

Colorectal cancer is the third most common cancer in the UK ( 38,000 new cases/annum), with 50% mortality rates. Radioimmunotherapy (RIT), the use of antibodies for sustained targeting of therapeutic radionuclides to the tumour, increases specificity of treatment and reduces systemic toxicity. Using antibodies that bind to carcinoembryonicantigen (CEA), overexpressed in colorectal tumours, we have shown RIT responses in pre-clinical and clinical studies. However, tumours have a tendency to regrow, because of non-uniform radiation dose delivery to cancer cells, and their differential sensitivity to radioactivity. This is aggravated by both the heterogeneous microenvironment and mutated genotype of the cells, which affect how tumours respond to ionising radiation. This treatment failure necessitates a combination therapy to significantly enhance RIT radiation damage. We previously combined RIT with vascular disprupting agents clinically, and obtained partial responses in patients refractory to standard treatment. We propose combining a humanised 131I?labeled anti-CEA antibody with a second antibody that also targets colorectal cancer. This antibody enhances sensitivity of tumours to external beam radiation clinically, and significantly augments RIT in our own pre-clinical studies. We plan to optimise timing and dosing schedules for this combined antibody therapy, for easy translation into early phase clinical trial within 3 years